Chlamydia trachomatis serovars A-L3 are the causative agents of hyperendemic blinding trachoma, a largely neglected disease of the developing world, and sexually transmitted infections (STI) that are epidemic worldwide. Chlamydial STI are risk factors for HIV and a cervical cancer co-factor. Control of these important human diseases is the long term goal of this project. Towards this end our goal is to develop a safe and efficacious live attenuated vaccine to prevent these diseases. The obligate intracellular life style, complex developmental biology, and antigenic structure of chlamydiae have severally hindered progress in vaccine development. A live-attenuated vaccine (LAV) will be beneficial in circumventing these difficulties. We have made a plasmid deficient trachoma strain and found it to be highly attenuated for the monkey eye. Ocular infection with the LAV is immunogenic and induces solid protective immunity to challenge with virulent trachoma organsims, Interestingly, LAV immunity was shown to be superior to natural infection mediated immunity. Paradoxially, vaccine mediated protective immunity was shown to be dependent of CD8 T cells which was in sharp contrast to natural immunity againt infection caused by virulent chlamydiae which is CD4 T cell dependent. These promising finding have led to NIAID support to purse an IND for the vaccine, contract a cGMP vaccine product, and the submission of phase I clinica protocol to conduct vaccine safety and immunogenicity studies in humans. A similar vaccine approach is being pursued in collaboration with Univeristy of Washington investigators using a female macaque chlamydial STD model.